Both sides will be considered outsiders to progress to the knockout stages, as they are joined in Group C by Leicester City and Napoli.
After suffering a 2-0 aggregate defeat to Benfica in Champions League qualification and dropping down into the Europa League group stage, Spartak Moscow will be hoping to reach the knockout rounds for the first time since 2010-11.
Rui Vitoria's men have had an inconsistent start to the new domestic campaign, winning and losing three games each in their opening seven league fixtures. The Red and Whites currently sit seventh in the Russian top flight and seven points behind league leaders Zenit St Petersburg.
Spartak head into their opening Europa League game with a poor record in European competitions, winning only four of their last 22 matches, excluding qualifiers.
They also failed to beat Wednesday's opponents Legia Warsaw in their previous two meetings against the Polish side back in 2011-12, losing 5-4 on aggregate in the Europa League qualifiers.
Vitoria's men will be up against it in Group C, but securing three points in midweek would be the perfect way for them to open their account and also put together a much-needed run of form across all competitions.
Like Spartak Moscow, Legia Warsaw also failed to progress in the Champions League qualifiers this season and have subsequently dropped down into the Europa League group stage.
Czeslaw Michniewicz's side were beaten 2-1 on aggregate by Dinamo Zagreb, before winning 4-3 on aggregate against Slavia Prague in their Europa League playoff, with striker Mahir Emreli scoring three of their goals across the two legs.
Legia Warsaw are one of eight reigning national champions in this season's Europa League and come into this tournament after clinching a record-breaking 15th league title last term.
Their domestic form has been impressive in recent years, though they have failed to impress in Europe, losing 11 of their last 16 matches in major UEFA competitions, excluding qualifiers.
Legia have also been poor away from home, suffering defeats in each of their last nine matches on the road by an aggregate score of 25-7. Success in Moscow on Wednesday is not out of the question, though they will need to replicate their domestic home form on the European scene if they are to come out on top at the Otkritie Arena.
As for Legia Warsaw, their only injury concern is with former Leicester midfielder Bartosz Kapustka, who continues to recover from a long-term knee injury.
The visitors are set to match Spartak with a 3-4-3 formation, which will likely see centre-backs Mateusz Wieteska, Artur Jedrzejczyk and Maik Nawrocki shielding 41-year-old former Southampton and Rangers goalkeeper Artur Boruc.
Azerbaijan international Emreli, who has scored six goals in 13 appearances across all competitions so far this season, is expected to lead the line up front and could be supported by fellow forwards Rafa Lopes and Luquinhas.
Spartak Moscow possible starting lineup:
Maksimenko; Rasskazov, Dzhikiya, Gigot; Moses, Umyarov, Zobnin, Ayrton; Ponce, Sobolev, Promes
Legia Warsaw possible starting lineup:
Boruc; Wieteska, Jedrzejczyk, Nawrocki; Johansson, Slisz, Martins, Mladenovic; Lopes, Luquinhas; Emreli
We say: Spartak Moscow 1-1 Legia Warsaw
Both Spartak Moscow and Legia Warsaw will view this fixture as a must-win game if they are to have any chance of advancing into the Europa League knockout stages.
However, with little to separate the two teams, a score draw could be on the cards at the Otkritie Arena.
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